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Carcinoma cells misuse the host tissue damage response to invade the brain.

Chuang HN, van Rossum D, Sieger D, Siam L, Klemm F, Bleckmann A, Bayerlová M, Farhat K, Scheffel J, Schulz M, Dehghani F, Stadelmann C, Hanisch UK, Binder C, Pukrop T - Glia (2013)

Bottom Line: Here we report that this is a fatal side effect of a physiological damage response of the brain tissue.While the glial damage response intended to protect the brain from intrusion of benign epithelial cells by inducing apoptosis, it proved ineffective against various malignant cell types.They did not undergo apoptosis and actually exploited the local tissue reaction to invade instead.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology/Oncology, University Medical Center, Göttingen, Germany.

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CXCR4 expression in astrocytes and microglia in human brain metastasis samples. (A) qRT-PCR results of cxcr4 illustrated by the ΔCt method. Human cerebral lung (L met) and breast cancer (B met) metastases samples demonstrate a marked expression of CXCR4 in contrast to the benign epithelial cell line hTERT. Line represents the mean and each dot represents the mean value of triplicate analyses with n ≥ 15. (B) Gene expression of cxcr4 is visualized using boxplots across all samples for the three different cxcr4 probes (209201_x_at, 217028_at, 211919_s_at). Samples are ordered by means of cxcr4 gene expression. Black: normal brain tissues, red: cerebral breast metastases, and blue: cerebral lung metastases. (C–E) Expression and localization of CXCR4 were analyzed in normal brains, cerebral metastasis of breast and lung cancer samples by immunohistochemistry. In normal brains, CXCR4 was undetectable (C), whereas in cerebral metastases, CXCR4 expression was detectable in the metastatic cells, the metastatic stroma, and especially in astrocytes in the gliosis region adjacent to the tumor cells (D and E) (scale bars represent 20 µm, in the left panel 200 µm). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
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fig07: CXCR4 expression in astrocytes and microglia in human brain metastasis samples. (A) qRT-PCR results of cxcr4 illustrated by the ΔCt method. Human cerebral lung (L met) and breast cancer (B met) metastases samples demonstrate a marked expression of CXCR4 in contrast to the benign epithelial cell line hTERT. Line represents the mean and each dot represents the mean value of triplicate analyses with n ≥ 15. (B) Gene expression of cxcr4 is visualized using boxplots across all samples for the three different cxcr4 probes (209201_x_at, 217028_at, 211919_s_at). Samples are ordered by means of cxcr4 gene expression. Black: normal brain tissues, red: cerebral breast metastases, and blue: cerebral lung metastases. (C–E) Expression and localization of CXCR4 were analyzed in normal brains, cerebral metastasis of breast and lung cancer samples by immunohistochemistry. In normal brains, CXCR4 was undetectable (C), whereas in cerebral metastases, CXCR4 expression was detectable in the metastatic cells, the metastatic stroma, and especially in astrocytes in the gliosis region adjacent to the tumor cells (D and E) (scale bars represent 20 µm, in the left panel 200 µm). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Mentions: Since we detected remarkable expression of cxcr4 in all of the five investigated human cerebral metastases of breast and lung carcinomas (Fig. 7A), we assessed the relevance of our qRT-PCR results in external gene sets, one from normal brain autopsies (GSE5389; n = 11), a second from breast (GSE14017, GSE14018; n = 22), and the third from lung adenocarcinoma brain metastasis (GSE14108; n = 28). As expected, the normal brain samples revealed the lowest expression, whereas cxcr4 expression in lung and breast metastases demonstrated a wide range, including samples with very high expression levels (Fig. 7B). Interestingly, the ligand cxcl12 was not upregulated in comparison to normal brain (Supp. Info. Fig. 4). Next, we analyzed the CXCR4 protein localization in normal brain tissue and cerebral metastases. First, our histological findings confirmed the gene expression pattern. While we detected no CXCR4 expression in normal tissue at all, the metastasis samples demonstrated an expression ranging from absence to very high levels. Most importantly, in samples with evaluable adjacent brain tissue, we discovered CXCR4 expression in the gliosis region next to the metastatic tissue in 80% of breast and 68.8% of lung cancer cerebral metastasis (Table1; Fig. 7C–E).


Carcinoma cells misuse the host tissue damage response to invade the brain.

Chuang HN, van Rossum D, Sieger D, Siam L, Klemm F, Bleckmann A, Bayerlová M, Farhat K, Scheffel J, Schulz M, Dehghani F, Stadelmann C, Hanisch UK, Binder C, Pukrop T - Glia (2013)

CXCR4 expression in astrocytes and microglia in human brain metastasis samples. (A) qRT-PCR results of cxcr4 illustrated by the ΔCt method. Human cerebral lung (L met) and breast cancer (B met) metastases samples demonstrate a marked expression of CXCR4 in contrast to the benign epithelial cell line hTERT. Line represents the mean and each dot represents the mean value of triplicate analyses with n ≥ 15. (B) Gene expression of cxcr4 is visualized using boxplots across all samples for the three different cxcr4 probes (209201_x_at, 217028_at, 211919_s_at). Samples are ordered by means of cxcr4 gene expression. Black: normal brain tissues, red: cerebral breast metastases, and blue: cerebral lung metastases. (C–E) Expression and localization of CXCR4 were analyzed in normal brains, cerebral metastasis of breast and lung cancer samples by immunohistochemistry. In normal brains, CXCR4 was undetectable (C), whereas in cerebral metastases, CXCR4 expression was detectable in the metastatic cells, the metastatic stroma, and especially in astrocytes in the gliosis region adjacent to the tumor cells (D and E) (scale bars represent 20 µm, in the left panel 200 µm). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
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Related In: Results  -  Collection

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fig07: CXCR4 expression in astrocytes and microglia in human brain metastasis samples. (A) qRT-PCR results of cxcr4 illustrated by the ΔCt method. Human cerebral lung (L met) and breast cancer (B met) metastases samples demonstrate a marked expression of CXCR4 in contrast to the benign epithelial cell line hTERT. Line represents the mean and each dot represents the mean value of triplicate analyses with n ≥ 15. (B) Gene expression of cxcr4 is visualized using boxplots across all samples for the three different cxcr4 probes (209201_x_at, 217028_at, 211919_s_at). Samples are ordered by means of cxcr4 gene expression. Black: normal brain tissues, red: cerebral breast metastases, and blue: cerebral lung metastases. (C–E) Expression and localization of CXCR4 were analyzed in normal brains, cerebral metastasis of breast and lung cancer samples by immunohistochemistry. In normal brains, CXCR4 was undetectable (C), whereas in cerebral metastases, CXCR4 expression was detectable in the metastatic cells, the metastatic stroma, and especially in astrocytes in the gliosis region adjacent to the tumor cells (D and E) (scale bars represent 20 µm, in the left panel 200 µm). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Mentions: Since we detected remarkable expression of cxcr4 in all of the five investigated human cerebral metastases of breast and lung carcinomas (Fig. 7A), we assessed the relevance of our qRT-PCR results in external gene sets, one from normal brain autopsies (GSE5389; n = 11), a second from breast (GSE14017, GSE14018; n = 22), and the third from lung adenocarcinoma brain metastasis (GSE14108; n = 28). As expected, the normal brain samples revealed the lowest expression, whereas cxcr4 expression in lung and breast metastases demonstrated a wide range, including samples with very high expression levels (Fig. 7B). Interestingly, the ligand cxcl12 was not upregulated in comparison to normal brain (Supp. Info. Fig. 4). Next, we analyzed the CXCR4 protein localization in normal brain tissue and cerebral metastases. First, our histological findings confirmed the gene expression pattern. While we detected no CXCR4 expression in normal tissue at all, the metastasis samples demonstrated an expression ranging from absence to very high levels. Most importantly, in samples with evaluable adjacent brain tissue, we discovered CXCR4 expression in the gliosis region next to the metastatic tissue in 80% of breast and 68.8% of lung cancer cerebral metastasis (Table1; Fig. 7C–E).

Bottom Line: Here we report that this is a fatal side effect of a physiological damage response of the brain tissue.While the glial damage response intended to protect the brain from intrusion of benign epithelial cells by inducing apoptosis, it proved ineffective against various malignant cell types.They did not undergo apoptosis and actually exploited the local tissue reaction to invade instead.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology/Oncology, University Medical Center, Göttingen, Germany.

Show MeSH
Related in: MedlinePlus